CN102120724A

CN102120724A - 5-amino-4-hydroxy-7-benzyl-8-methylnonanamide derivative, preparation method thereof and application thereof in medicines

Info

Publication number: CN102120724A
Application number: CN2010100023791A
Authority: CN
Inventors: 邓炳初; 吴清泉; 潘耀辉; 申大为
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2010-01-12
Filing date: 2010-01-12
Publication date: 2011-07-13

Abstract

The invention relates to a 5-amino-4-hydroxy-7-benzyl-8-methylnonanamide derivative, a preparation method thereof and application thereof in medicines. Specifically, the invention relates to a novel 5-amino-4-hydroxy-7-benzyl-8-methylnonanamide derivative shown in a general formula (I) in the specification, a preparation method thereof, and medicinal composition containing the derivative as well as application of the medicinal composition as a therapeutical agent, particularly as a Renin inhibitor and medicaments for treating and resisting high blood pressure and diseases related to Renin activities, wherein all substituent groups in the general formula (1) are identical to those defined in the specification.

Description

5-amino-4-hydroxy-7-benzyl-8-methyl pelargonamide analog derivative, its preparation method and in pharmaceutically application

Technical field

The pharmaceutical composition that the present invention relates to a kind of new 5-amino-4-hydroxy-7-benzyl-8-methyl pelargonamide analog derivative, its preparation method and contain this derivative with and as therapeutical agent particularly as renin inhibitor with as the purposes with the medicine of renin activity diseases related such as hypertension.

Background technology

Aspartate protease (Aspartic Proteinase) is a class important protein lytic enzyme, participates in the metabolism and the biological regulating and controlling effect of body.In general, their active centre is made up of the catalytic asparagicacid residue of two high conservatives.Common aspartate protease comprises: stomach en-, feritin (Renin), beta-secretase (beta-amyloyd precursor protein lyase, β-site amyloid precursor protein cleaving enzyme, BACE), hiv protease, human T-leukemia virus's proteolytic enzyme etc.Their its generations with numerous disease are relevant, as: in the essential hypertension people, because the katalysis of feritin makes the angiotensin I level raise; Generally believe at present that in addition one of alzheimer's disease main pathogenesis is to form owing to abnormal deposition that BACE acts on the product amyloid beta behind the amyloid precursor protein.In addition, human immunodeficiency virus and human T-leukemia virus all need the participation of aspartate protease separately in its ripening process.

Feritin (Renin), claim Angiotensinogenase again, it is synthetic and release by renal glomerulus, in blood, proangiotensin is cracked into decapeptide angiotensin I (angiotensin I subsequently, Ang I), at angiotensin-converting enzyme (angiotensin converting enzyme, ACE) under the effect, AngI is cracked into octapeptide Angiotensin II (angiotensin II, Ang II), the AngII of high biological activity can shrink direct rising blood pressure by arteries, also can discharge the aldosterone blood pressure that raises indirectly by regulating suprarenal gland.This begins to the regulation mechanism that generates till the aldosterone from feritin, be called renin-angiotensin-aldosterone system (Renin-angiotension-aldosterone system, RAAS).

Renin-angiotensin-aldosterone system (RAAS) is keying action target spot (the Nature Reviews Drug Discovery 2002 such as Zaman M.A. of pharmacological agent cardiovascular system diseases; 1:621-36), the generation and the blocking-up angiotensin-ii receptor of the secretion that it can be by suppressing feritin, activity, prevention Angiotensin II are realized.At present, the blocker of angiotensin-convertion enzyme inhibitor (ACEi) and angiotensin receptor (Angiotensin AT1 receptor blockers, ARBS) all go on the market, some medicine becomes antihypertensive a line medicine (Su Dingfeng etc., Chinese Journal of New Drugs and Clinical Remedies 2001; 20 (2) 139-42).But also there are some problems in current ACEi inhibitor and ABRs, not exclusively block as the non-specific RAAS of the causing system of ACEi, cross high side effect thereby produce as dry cough, headache, blood potassium.Because feritin is directly regulated the initial link in the RAAS system---AngI generates, and vasotonia have high degree of specificity for endogenous, is the research focus that acts on the RASS medicine therefore always.

In addition, by suppressing feritin blocking-up RASS except energy is hypotensive, can also reduce trouble diabetes and other cardiovascular disease risk of causing because of hypertension.As block RAAS and can be used for treating liver, renal fibrosis (Contrib Nephrol.2001 such as Gaedeke J; 135:153-60, World JGastroenterol.2009 such as Regina M.P.; 15 (21): 2579-86), atherosclerosis, myocardial hypertrophy, myocardial fibrosis, diastolic dysfunction, diabetic complication diseases such as (as ephrosis, eye diseases).

First-generation renin inhibitor is a peptide class substrate analogue, and the body internal stability is poor, and action time is short, can only the enteron aisle external administration (people J Biol Chem such as Cumin F, 1985; 260 (16): 9154-57.).After this carry out chemically modified on its basis, synthesized the oral plan peptide of s-generation class renin inhibitor, as CGP-29287, CGP-38560, Rui Mijilun (Remikiren, Ro425892), Yi Najilun (Enalkiren, A64662) (WoodJ M etc., Hypertension, 1985; 7,797-803; Expert Opin Ther Patents2003 such as Maibaum J; 13,589-603; Wood J M etc., J Cardiovasc Pharmacol 1989; 14,221-26).But in the experimentation on animals, its oral administration biaavailability extreme difference (＜2%), the transformation period is short, greatly limits its antihypertensive activity performance, thereby can't be applied to clinical.In recent years, along with the development of medicament research and development technology, design the non-peptide micromolecular of third generation renin inhibitor.Disclosed relevant patent has: WO8805049, EP0678503, WO2004002483, WO2004002957, WO2005051895, WO2005070871, WO2006069788, WO2006103277, WO2007031557 etc.Wherein, the renin inhibitor of having developed at present, because molecular weight is bigger, human bioavailability is low, therefore, improves actively, improves pharmacokinetic property and be the main direction of studying of renin inhibitor from now on.

Purpose of the present invention is exactly to keep the better active while of inhibitor, and the medicine that improves compound is for character, and a kind of clinical medicine that feritin suppresses active and can be used for hypertension etc. and the treatment or the alleviation of renin activity diseases related that has is provided.

Summary of the invention

In order to overcome the deficiencies in the prior art part, the object of the present invention is to provide the 5-amino-4-hydroxy shown in a kind of general formula (I)-7-benzyl-8-methyl pelargonamide analog derivative, and their tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmacy acceptable salt and metabolite or prodrug:

Wherein:

Ring A is selected from aryl or heteroaryl, is preferably phenyl, furyl, thienyl, pyridyl, pyrryl, pyrimidyl, pyrazinyl;

R ¹Be selected from hydrogen atom or alkyl, wherein said alkyl is optional further to be replaced by one or more substituting groups that are selected from halogen or alkoxyl group;

R ²Be selected from hydrogen atom or alkyl;

R ³Be selected from hydrogen atom or alkyl;

R ⁴, R ⁵, R ⁶And R ⁷Be selected from separately hydrogen atom, alkyl, alkoxyl group, hydroxyl, halogen, cyano group, nitro ,-NR ⁸R ⁹,-CO ₂NR ⁸R ⁹,-SO ₂NR ⁸R ⁹,-COR ¹⁰,-SO ₂R ¹⁰, carboxylic acid or carboxylicesters;

R ⁸Or R ⁹Be selected from hydrogen atom or alkyl separately;

Perhaps, R ⁸Or R ⁹Coupled N atom forms 3～8 yuan of heterocyclic radicals together, wherein said 3～8 yuan of rings contain 1～2 N, O or S (O) n heteroatoms, and described 3～8 yuan of rings optional further by one or more alkyl, alkoxyl group, halogen, carbonyl, aryl, benzyl ,-NR ¹¹R ¹²,-CO ₂NR ¹¹R ¹²,-SO ₂NR ¹¹R ¹²,-COR ¹⁰,-SO ₂R ¹⁰, carboxylic acid or carboxylicesters substituting group replace;

R ¹⁰Be selected from hydrogen atom, alkyl or aryl;

R ¹¹Or R ¹²Be selected from hydrogen atom or alkyl separately; And

N is 0,1 or 2.

Preferred compound of the present invention is the compound shown in the general formula (II) or its pharmacy acceptable salt:

Wherein:

R ²Be selected from hydrogen atom or alkyl;

R ³Be selected from hydrogen atom or alkyl;

R ⁸Or R ⁹Be selected from hydrogen atom or alkyl separately;

R ¹⁰Be selected from hydrogen atom, alkyl or aryl;

R ¹¹Or R ¹²Be selected from hydrogen atom or alkyl separately; And

N is 0,1 or 2.

General formula (I) and (II) compound be depicted as 5-amino-4-hydroxy-7-benzyl-8-methyl pelargonamide analog derivative, its compound group position naming number is identical, sees general formula (I).

Therefore general formula (I) compound has at least 4 unsymmetrical carbons, can exist or exist as the mesomeride compound with the form of the mixture of optically pure diastereomer, non-enantiomer mixture, diastereomer racemic modification, non-mapping racemic modification.The present invention includes all these forms.The mixture of non-enantiomer mixture, non-mapping racemic modification or non-mapping racemic modification can pass through ordinary method, for example waits with HPLC by column chromatography, tlc and separates.

Typical compound of the present invention includes, but are not limited to:

Or its pharmacy acceptable salt.

The present invention relates to the preparation method of general formula (I) compound or its pharmacy acceptable salt, this method comprises:

General formula (IA) compound and replacement primary amine reaction, and under suitable condition, comprise the protecting group PG that sloughs amine under alkaline condition, acidic conditions or the catalytic hydrogenation condition, obtain general formula (I) compound.

Wherein: ring A, R ¹～R ⁷Definition such as general formula (I) described in; PG is the amido protecting group, is selected from tert-butoxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, trifluoroacetyl group, formyl radical, p-toluenesulfonyl, trityl, phthalimide-based or 2-xenyl-2-third oxygen carbonyl, is preferably tert-butoxycarbonyl.

Further, the present invention relates to the preparation method of general formula (II) compound or its pharmacy acceptable salt, this method comprises:

General formula (IB) compound and replacement primary amine reaction, and under suitable condition, comprise the protecting group PG that sloughs amine under alkaline condition, acidic conditions or the catalytic hydrogenation condition, obtain general formula (II) compound.

Described pharmacy acceptable salt of the present invention is The compounds of this invention and is selected from following sour formed salt: oxysuccinic acid, lactic acid, toxilic acid, hydrochloric acid, methylsulfonic acid, sulfuric acid, phosphoric acid, citric acid, fumaric acid, acetate or trifluoroacetic acid are preferably fumaric acid.

Another aspect of the present invention relates to The compounds of this invention or the purposes of its pharmacy acceptable salt in the medicine of preparation renin inhibitor.

Further, the invention still further relates to The compounds of this invention or its pharmacy acceptable salt in the medicine of the preparation disease relevant with feritin purposes, wherein relevant with feritin disease comprises: hypertension, atherosclerosis, the instability mode coronary syndrome, congestive heart failure, myocardial hypertrophy, myocardial fibrosis, infraction back myocardosis, the instability mode coronary syndrome, diastolic dysfunction, chronic nephropathy, hepatic fibrosis, the complication that diabetes cause is (as ephrosis, vascular disease and neuropathy), coronary artery disease, the restenosis of postangioplasty, eye-chamber pressure raises, glaucoma, the abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimer's disease, dull-witted, anxiety state and cognitive disorders.

Further, another aspect of the present invention relates to a kind of pharmaceutical composition, and it contains The compounds of this invention or its pharmacy acceptable salt for the treatment of effective dose, and pharmaceutically useful carrier or vehicle.The purposes of this pharmaceutical composition in the medicine of preparation renin inhibitor.This pharmaceutical composition in the medicine of the preparation treatment disease relevant with feritin purposes, wherein relevant with feritin disease comprises: hypertension, atherosclerosis, the instability mode coronary syndrome, congestive heart failure, myocardial hypertrophy, myocardial fibrosis, infraction back myocardosis, the instability mode coronary syndrome, diastolic dysfunction, chronic nephropathy, hepatic fibrosis, the complication that diabetes cause, as ephrosis, vascular disease and neuropathy, coronary artery disease, the restenosis of postangioplasty, eye-chamber pressure raises, glaucoma, the abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimer's disease, dull-witted, anxiety state and cognitive disorders.

On the other hand, compound of the present invention or its pharmacy acceptable salt contain the pharmaceutical composition of described compound, are used as the medicine of renin inhibitor.

On the other hand, compound of the present invention or its pharmacy acceptable salt contain the pharmaceutical composition of described compound, as the medicine of treatment with the renin activity diseases associated.Wherein with the renin activity diseases associated as mentioned above.

On the other hand, the present invention relates to a kind of method that suppresses feritin, this method comprises compound of the present invention or its pharmacy acceptable salt of the effective therapeutic dose of patient that needs treatment, contains the pharmaceutical composition of described compound.

On the other hand, the present invention relates to the method for a kind of treatment and renin activity diseases associated, this method comprises compound of the present invention or its pharmacy acceptable salt of the effective therapeutic dose of patient that needs treatment, contains the pharmaceutical composition of described compound.Wherein with the renin activity diseases associated as mentioned above.

Detailed description of the invention

Unless the phase counter-statement is arranged, otherwise the following term that is used in specification sheets and claims has following implication.

" alkyl " refers to saturated aliphatic hydrocarbon group, comprises the straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 10 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl or amyl group etc.The low alkyl group that more preferably contains 1 to 4 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, be independently selected from alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NR ⁸R ⁹,-CO ₂NR ⁸R ⁹,-SO ₂NR ⁸R ⁹,-COR ¹⁰,-SO ₂R ¹⁰, carboxylic acid or carboxylicesters.

" aryl " refers to comprise 6 to 14 yuan of full carbon monocycles or fused polycycle (just share and adjoin the right ring of carbon atom) group, many rings (being its ring that the has phase adjacency pair carbon atom) group with conjugated πDian Zi system.Preferably contain 6 to 10 yuan, for example phenyl, naphthyl and anthryl etc.More preferably 6 yuan, phenyl etc. for example.Aryl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NR ⁸R ⁹,-CO ₂NR ⁸R ⁹,-SO ₂NR ⁸R ⁹,-COR ¹⁰,-SO ₂R ¹⁰, carboxylic acid or carboxylicesters.

" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.Be preferably 5 yuan or 6 yuan of ring heteroaryls, for example furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Heteroaryl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NR ⁸R ⁹,-CO ₂NR ⁸R ⁹,-SO ₂NR ⁸R ⁹,-COR ¹⁰,-SO ₂R ¹⁰, carboxylic acid or carboxylicesters.

The quantity that " 3～8 yuan of heterocyclic radicals " refers to constitute annular atoms is 3～8 yuan, constitute in the atom that encircles and contain one or more N, O or S (O) n heteroatoms, can contain 1～2 two key in the ring, cyclic group for the non-aromatic of monocycle or dicyclo, constitute when containing nitrogen-atoms in the atom that encircles, can stretch out associative key from nitrogen-atoms.Be preferably 4～6 yuan of heterocyclic radicals, more preferably 5～6 yuan, for example pyrrolidyl, piperidyl or piperazinyl etc.3～8 yuan of heterocyclic radicals can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NR ⁸R ⁹,-CO ₂NR ⁸R ⁹,-SO ₂NR ⁸R ⁹,-COR ¹⁰,-SO ₂R ¹⁰, carboxylic acid or carboxylicesters.

" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted cycloalkyl), the definition of alkyl is as mentioned above.For example methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, be independently selected from into alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NR ⁸R ⁹,-CO ₂NR ⁸R ⁹,-SO ₂NR ⁸R ⁹,-COR ¹⁰,-SO ₂R ¹⁰, carboxylic acid or carboxylicesters.

" hydroxyl " refers to-the OH group.

" halogen " refers to fluorine, chlorine, bromine or iodine.

" amino " refers to-NH ₂

" cyano group " refers to-CN.

" nitro " refers to-NO ₂

" benzyl " refers to-CH ₂-(phenyl).

" carbonyl " refers to=O.

" tert-butoxycarbonyl " refers to (CH ₃) ₃O-C (=O)-.

" carbobenzoxy-(Cbz) " refers to (phenyl)-CH ₂-C (=O)-.

" ethanoyl " refers to CH ₃C (=O)-.

" trifluoroacetyl group " refers to CF ₃C (=O)-.

" formyl radical " refer to HC (=O)-.

" p-toluenesulfonyl " refers to 4-CH ₃-(phenyl)-SO ₂-.

" trityl " refers to (phenyl) ₃-C-.

" carboxylic acid " refer to-C (=O) OH.

" carboxylicesters " refer to-C (=O) O (alkyl, cycloalkyl, aryl or heteroaryl).

" phthalimide-based " refers to

" 2-xenyl-2-third oxygen carbonyl " refers to

" choose wantonly " or " randomly " mean describe subsequently ground incident or environment can but needn't take place, this explanation comprises that this incident or environment take place or spot occasion not.For example, " the optional heterocyclic group that is replaced by alkyl " mean alkyl can but must not exist, this explanation comprises the situation that situation that heterocyclic group is replaced by alkyl and heterocyclic group are not replaced by alkyl.

" pharmaceutical composition " represent on one or more compounds described herein or its physiology/mixture of pharmacy acceptable salt or prodrug and other chemical compositions, and other components are physiology/pharmaceutically useful carrier and vehicle for example.The purpose of pharmaceutical composition is to promote the administration of compound to organism.

N wherein, R ⁸～R ¹⁰Definition such as general formula (I) described in.

The synthetic method of The compounds of this invention

In order to finish purpose of the present invention, the present invention adopts following technical scheme:

The preparation method of the described compound of general formula of the present invention (I) or its pharmacy acceptable salt may further comprise the steps:

Wherein: ring A, R ¹～R ⁷Definition such as general formula (II) described in; PG is the amido protecting group, is selected from tert-butoxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, trifluoroacetyl group, formyl radical, p-toluenesulfonyl, trityl, phthalimide-based or 2-xenyl-2-third oxygen carbonyl, is preferably tert-butoxycarbonyl.

Embodiment

Be used to further describe the present invention below in conjunction with embodiment, but these embodiment and unrestricted scope of the present invention.

Embodiment

The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS).NMR displacement (δ) provides with 1,000,000/(ppm) unit.The mensuration of NMR is to use the BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterated methanol (CD ₃OD), deuterochloroform (CDCl ₃), deuterated dimethyl sulfoxide (DMSO-D ₆), in be designated as tetramethylsilane (TMS), chemical shift is with 10 ^-6(ppm) provide as unit.

The mensuration of MS FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Therm, model: FinniganLCQ advantage MAX).

IC ₅₀The mensuration of value is with Novostar microplate reader (German BMG company).

The tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) is used adopts is 0.15mm～0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm～0.5mm.

Column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier.

Starting raw material of the present invention is known, and can buy on market, buys from ABCR GmbH﹠amp; Co.KG, Acros Organics, companies such as Aldrich Chemical Company perhaps can adopt or synthesize according to methods known in the art.

Do not have specified otherwise among the embodiment, reaction is all carried out under argon atmospher or nitrogen atmosphere.

Argon atmospher or nitrogen atmosphere are meant that reaction flask connects an about 1L volumetrical argon gas or nitrogen balloon.

Nitrogen atmosphere is meant that reaction flask connects an about 1L volumetrical hydrogen balloon.

Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument are used in the pressure hydration reaction.

Hydrogenation vacuumizes usually, charges into hydrogen, repeatable operation 3 times.

Microwave reaction uses CEM Discover-S 908860 type microwave reactors.

Do not have specified otherwise among the embodiment, the solution in the reaction is meant the aqueous solution.

Do not have specified otherwise among the embodiment, the temperature of reaction is a room temperature.

Room temperature is optimum temperature of reaction, is 20 ℃～30 ℃.

Tlc is adopted in the monitoring of reaction process among the embodiment, the system of reacting employed developping agent comprises: methylene dichloride and methanol system, normal hexane and ethyl acetate system, sherwood oil and ethyl acetate system, acetone, the volume ratio of solvent is according to different adjusting of polarity of compound.

The system of the eluent of column chromatography comprises: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, C: the normal hexane system, the volume ratio of solvent also can add a spot of ammoniacal liquor and acetic acid etc. and regulate according to different adjusting of polarity of compound.

Preparation embodiment:

Embodiment 1

(2S, 4S, 5S, 7S)-5-amino-4-hydroxy-2-sec.-propyl-N-((S)-2-methoxyl group-1-phenylethyl)-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide fumarate

The first step

(S)-2-(dibenzyl amino)-2-phenylacetic acid benzyl ester

Under 45 ℃, with salt of wormwood (2.76g, 0.02mol) and sodium hydroxide (0.80g, 0.02mol) be dissolved in the 20mL water, adding (S)-2-amino-2-phenylacetic acid 1a (1.51g, 0.01mol), dropping benzyl bromine 1b (4.10mL, 0.035mol), stirring reaction 12 hours.In reaction solution, add 100mL water, with ethyl acetate extraction (150mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying filters, filtrate decompression concentrates, (eluent: the gained resistates system B of suitable proportion) obtains title product (S)-2-(dibenzyl amino)-2-phenylacetic acid benzyl ester 1c (4.30g, white oily matter) crude product with purification by silica gel column chromatography.

MS?m/z(ESI)：422[M+1]

Second step

(S)-2-(dibenzyl amino)-2-phenylethyl alcohol

Under the ice bath, with (S)-2-(dibenzyl amino)-2-phenylacetic acid benzyl ester 1c (4.30g 0.01mol) is dissolved in the 25mL tetrahydrofuran (THF), add lithium aluminum hydride (0.95g, 0.025mol), stirring reaction 12 hours.In reaction solution, add 2mL water, the sodium hydroxide solution that adds 4mL 10% with ethyl acetate extraction (100mL * 3), merges organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with purification by silica gel column chromatography (eluent: the gained resistates system B of suitable proportion), obtain title product (S)-2-(dibenzyl amino)-2-phenylethyl alcohol 1d (3.01g, light yellow oil), productive rate: 94.6%.

MS?m/z(ESI)：318[M+1]

The 3rd step

(S)-and N, N-dibenzyl-2-methoxyl group-1-phenyl-ethyl amine

Under the ice bath, (3.01g 9.5mmol) is dissolved in the 25mL tetrahydrofuran (THF) with (S)-2-(dibenzyl amino)-2-phenylethyl alcohol 1d, the sodium hydride of adding 60% (0.57g, 14.2mmol), stirring reaction 3 hours, (0.88mL 14.2mmol), continues to stir 12 hours to drip methyl iodide.In reaction solution, add 2mL water, with dichloromethane extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with purification by silica gel column chromatography (eluent: the gained resistates system B of suitable proportion), obtain title product (S)-N, N-dibenzyl-2-methoxyl group-1-phenyl-ethyl amine 1e (3.00g, light yellow oil), productive rate: 95.5%.

MS?m/z(ESI)：332[M+1]

The 4th step

(S)-2-methoxyl group-1-phenyl-ethyl amine

With (S)-N, (3.00g 9.1mmol) is dissolved in the 25mL tetrahydrofuran (THF) N-dibenzyl-2-methoxyl group-1-phenyl-ethyl amine 1e, adds palladium/carbon (1.20g, 10%), hydrogen exchange three times, 45 ℃ of following stirring reactions 12 hours.Filter, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system A of suitable proportion) obtains title product (S)-2-methoxyl group-1-phenyl-ethyl amine 1f (1.10g with purification by silica gel column chromatography, colourless liquid), productive rate: 80.0%.

MS?m/z(ESI)：152[M+1]

The 5th step

(3S, 5S, 6S, 8S)-and 6-hydroxyl-8-((S)-2-methoxyl group-1-phenylethyl carbamyl)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester

Under 80 ℃, with (1S, 3S)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-4-methyl amyl carboxylamine tertiary butyl ester 1g (employing known method Journalof Organic Chemistry, 2006,71 (13), 4766-4777 preparation and get) (147mg, 0.28mmol) be dissolved in the 2mL triethylamine, add (S)-2-methoxyl group-1-phenyl-ethyl amine 1f (125mg, 0.83mmol) and 2 hydroxy pyrimidine (79mg, 0.83mmol), stirring reaction 18 hours.Concentrating under reduced pressure, with purification by silica gel column chromatography (eluent: the gained resistates system A of suitable proportion), obtain title product (3S, 5S, 6S, 8S)-6-hydroxyl-8-((S)-2-methoxyl group-1-phenylethyl carbamyl)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 1h (25mg, faint yellow solid), productive rate: 13.2%.

MS?m/z(ESI)：687[M+1]

The 6th step

(2S, 4S, 5S, 7S)-5-amino-4-hydroxy-2-sec.-propyl-N-((S)-2-methoxyl group-1-phenylethyl)-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide

Under the ice bath, with (3S, 5S, 6S, 8S)-6-hydroxyl-8-((S)-2-methoxyl group-1-phenylethyl carbamyl)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 1h (25mg, 0.036mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH＞7, with dichloromethane extraction (10mL * 3), merge organic phase, water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, (eluent: the gained resistates system A of suitable proportion) obtains title product (2S, 4S to prepare the plate purifying with thin layer, 5S, 7S)-and 5-amino-4-hydroxy-2-sec.-propyl-N-((S)-2-methoxyl group-1-phenylethyl)-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide 1j (18mg, faint yellow solid), productive rate: 84.5%.

MS?m/z(ESI)：587[M+1]

The 7th step

With (2S, 4S, 5S, 7S)-5-amino-4-hydroxy-2-sec.-propyl-N-((S)-2-methoxyl group-1-phenylethyl)-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide 1j (18mg, 0.031mmol) be dissolved in the 2mL methyl alcohol, (2mg, 0.015mmol) stirring reaction is 10 minutes to add fumaric acid.The reaction solution concentrating under reduced pressure, obtain title product (2S, 4S, 5S, 7S)-5-amino-4-hydroxy-2-sec.-propyl-N-((S)-2-methoxyl group-1-phenylethyl)-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide fumarate 1 (19mg, faint yellow solid), productive rate: 95.0%.

MS?m/z(ESI)：587[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)δ7.43-7.26(m，5H)，6.79-6.67(m，3H)，5.22(m，1H)，4.12(t，J＝6.4Hz，2H)，3.85(s，3H)，3.73-3.65(m，2H)，3.60(t，J＝6.4Hz，2H)，3.38(s，6H)，3.05(br.s，1H)，2.46-2.40(m，2H)，2.26(m，1H)，2.11(m，2H)，1.85(m，1H)，1.58(m，3H)，1.40-1.20(m，4H)，1.01-0.83(m，12H)

Embodiment 2

(2S, 4S, 5S, 7S)-5-amino-N-((S)-2-oxyethyl group-1-(4-p-methoxy-phenyl) ethyl)-4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide

The first step

(S)-2-amino-2-(4-hydroxy phenyl) methyl acetate hydrochloride

Under the ice bath, (2.36g 30mmol) is dissolved in the 50mL methyl alcohol, and (1.67g, 10mmol), stirring at room was reacted 2 hours, reflux 2 hours to add (S)-2-amino-2-(4-hydroxy phenyl) acetate 2a with ethyl chloroacetate.Add 2mL water in reaction solution, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, and obtains title product (S)-2-amino-2-(4-hydroxy phenyl) methyl acetate hydrochloride 2b (1.81g, white solid) crude product.

Second step

(S)-2-(t-butoxycarbonyl amino)-2-(4-hydroxy phenyl) methyl acetate

Under the ice bath, (1.81g 10mmol) is dissolved in the 15mL methylene dichloride with (S)-2-amino-2-(4-hydroxy phenyl) methyl acetate hydrochloride 2b, add triethylamine (2.02g, 20mmol) (3.27g, 15mmol), stirring reaction is 12 hours under the room temperature with two dimethyl dicarbonate butyl esters.In reaction solution, add 2mL water, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product (S)-2-(t-butoxycarbonyl amino)-2-(4-hydroxy phenyl) methyl acetate 2c (2.61g with purification by silica gel column chromatography, white solid), productive rate: 93.0%.

The 3rd step

(S)-2-(t-butoxycarbonyl amino)-2-(4-p-methoxy-phenyl) methyl acetate

Under the ice bath, with (S)-2-(t-butoxycarbonyl amino)-2-(4-hydroxy phenyl) methyl acetate 2c (2.61g, 9.3mmol) and salt of wormwood (1.93g, 14mmol) be dissolved in 10mL N, in the dinethylformamide, drip methyl iodide (1.45g, 10mmol), stirring reaction 12 hours under the room temperature.In reaction solution, add 2mL water, add 6M hydrochloric acid and regulate pH＞7, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with purification by silica gel column chromatography (eluent: the gained resistates system B of suitable proportion), obtain title product (S)-2-(t-butoxycarbonyl amino)-2-(4-p-methoxy-phenyl) methyl acetate 2d (1.80g, colorless oil), productive rate: 66.0%.

The 4th step

(S)-2-hydroxyl-1-(4-p-methoxy-phenyl) ethyl carbamic acid tertiary butyl ester

Under the ice bath, (1.80g 5.1mmol) is dissolved in the 50mL tetrahydrofuran (THF), and (233mg, 6.1mmol), stirring reaction is 12 hours under the room temperature to add lithium aluminum hydride with (S)-2-(t-butoxycarbonyl amino)-2-(4-p-methoxy-phenyl) methyl acetate 2d.In reaction solution, add 2mL water, filter, with ethyl acetate extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product (S)-2-hydroxyl-1-(4-p-methoxy-phenyl) ethyl carbamic acid tertiary butyl ester 2e (1.10g, faint yellow solid), productive rate: 67.5%.

The 5th step

(S)-2-oxyethyl group-1-(4-p-methoxy-phenyl) ethyl carbamic acid tertiary butyl ester

Under the ice bath, with (S)-2-hydroxyl-1-(4-p-methoxy-phenyl) ethyl carbamic acid tertiary butyl ester 2e (534mg, 2mmol) be dissolved in 50mLN, in the dinethylformamide, and the sodium hydride of adding 60% (88mg, 2.2mmol), stirring reaction 30 minutes, (343mg, 2.2mmol), room temperature continued stirring reaction 12 hours to add iodoethane.In reaction solution, add 2mL water, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product (S)-2-oxyethyl group-1-(4-p-methoxy-phenyl) ethyl carbamic acid tertiary butyl ester 2f (300mg with purification by silica gel column chromatography, colourless liquid), productive rate: 51.0%.

MS?m/z(ESI)：196[M+1-100]

The 6th step

(S)-2-oxyethyl group-1-(4-p-methoxy-phenyl) ethylamine hydrochloride

Under the ice bath, (300mg, (V/V=3: 1) in the mixed solvent, stirring at room was reacted 12 hours 1mmol) to be dissolved in 4mL tetrahydrofuran (THF) and concentrated hydrochloric acid with (S)-2-oxyethyl group-1-(4-p-methoxy-phenyl) ethyl carbamic acid tertiary butyl ester 2f.Concentrating under reduced pressure adds 50mL toluene, and concentrating under reduced pressure obtains title product (S)-2-oxyethyl group-1-(4-p-methoxy-phenyl) ethylamine hydrochloride 2g (190mg, yellow solid), productive rate: 96.0% once more.

MS?m/z(ESI)：191[M+1]

The 7th step

(3S, 5S, 6S, 8S)-and 8-((S)-2-oxyethyl group-1-(4-p-methoxy-phenyl) ethylamino formyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester

Under the ice bath, with (S)-2-oxyethyl group-1-(4-p-methoxy-phenyl) ethylamine hydrochloride 2g (190mg, 1mmol) be dissolved in the 5mL toluene, drip the toluene solution and the 5mL (1S of the trimethyl aluminium of 0.5mL2M, 3S)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-4-methyl amyl carboxylamine tertiary butyl ester 1g (174mg, toluene solution 0.32mmol), stirring reaction 12 hours.In reaction solution, add 2mL 1M hydrochloric acid, with dichloromethane extraction (30mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product (3S with purification by silica gel column chromatography, 5S, 6S, 8S)-8-((S)-2-oxyethyl group-1-(4-p-methoxy-phenyl) ethylamino formyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 2h (90mg, colorless oil), productive rate: 38.5%.

MS?m/z(ESI)：731[M+1]

The 8th step

Under the ice bath, with (3S, 5S, 6S, 8S)-8-((S)-2-oxyethyl group-1-(4-p-methoxy-phenyl) ethylamino formyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 2h (90mg, 0.12mmol) be dissolved in the 2mL methylene dichloride, add 4mL concentrated hydrochloric acid 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH＞7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, (eluent: the gained resistates system A of suitable proportion) obtains title product (2S, 4S to prepare the plate purifying with thin layer, 5S, 7S)-and 5-amino-N-((S)-2-oxyethyl group-1-(4-p-methoxy-phenyl) ethyl)-4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide 2 (27mg, faint yellow solid), productive rate: 35.0%.

MS?m/z(ESI)：631[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)δ7.34(d，J＝8.4Hz，2H)，7.30(s，1H)，6.92(s，J＝8.4Hz，2H)，6.86-6.72(m，3H)，5.09(m，1H)，4.12(t，J＝6.4Hz，2H)，3.82(s，3H)，3.70(s，3H)，3.68-3.49(m，7H)，3.35(s，3H)，2.70(m，1H)，2.46(m，2H)，2.33(m，2H)，2.08(m，2H)，1.90-1.49(m，5H)，1.19(t，J＝6.8Hz，3H)，0.98-0.78(m，12H)

Embodiment 3

(2S, 4S, 5S, 7S)-5-amino-N-((S)-1-(4-fluorophenyl)-2-methoxy ethyl)-4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide

The first step

(S)-2-amino-2-(4-fluorophenyl) methyl acetate hydrochloride

Under the ice bath, (2.50g 15mmol) is dissolved in the 80mL methyl alcohol, and (1.50mL, 22mmol), stirring at room was reacted 2 hours, back flow reaction 2 hours to drip thionyl chloride with (S)-2-amino-2-(4-fluorophenyl) acetate 3a.The reaction solution concentrating under reduced pressure obtains title product (S)-2-amino-2-(4-fluorophenyl) methyl acetate hydrochloride 3b (3.01g, faint yellow solid), productive rate: 90.9%.

Second step

(S)-2-(t-butoxycarbonyl amino)-2-(4-fluorophenyl) methyl acetate

Under the ice bath, (3.01g 14mmol) is dissolved in the 50mL water with (S)-2-amino-2-(4-fluorophenyl) methyl acetate hydrochloride 3b, add salt of wormwood (6.20g, 45mmol) (stirring reaction is 12 hours under the room temperature for 3.90g, tetrahydrofuran solution 18mmol) with 20mL two dimethyl dicarbonate butyl esters.Separatory, with ethyl acetate extraction (150mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying filters, filtrate decompression concentrates, obtain title product (S)-2-(t-butoxycarbonyl amino)-2-(4-fluorophenyl) methyl acetate 3c (3.60g, colorless oil), productive rate: 92.0%.

The 3rd step

(S)-1-(4-fluorophenyl)-2-hydroxyethyl carboxylamine tertiary butyl ester

Under the ice bath, (5.00g 131mmol) is dissolved in the 100mL ethanol, and Dropwise 5 0mL (S)-(stirring reaction is 12 hours under the room temperature for 7.50g, ethanolic soln 26mmol) for 2-(t-butoxycarbonyl amino)-2-(4-fluorophenyl) methyl acetate 3c with sodium borohydride.The reaction solution concentrating under reduced pressure, add 50mL water and 50mL ethyl acetate, with ethyl acetate extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product (S)-1-(4-fluorophenyl)-2-hydroxyethyl carboxylamine tertiary butyl ester 3d (5.50g, white solid), productive rate: 83.0%.

MS?m/z(ESI)：278[M+23]

The 4th step

(S)-1-(4-fluorophenyl)-2-methoxy ethyl carboxylamine tertiary butyl ester

Under-20 ℃, sodium hydride (0.45g with 60%, 11mmol) be dissolved in the 10mL tetrahydrofuran (THF), drip 10mL (S)-1-(4-fluorophenyl)-2-hydroxyethyl carboxylamine tertiary butyl ester 3d (2.01g, 7.8mmol) tetrahydrofuran solution, drip methyl iodide (1.60g, 11.7mmol), 0 ℃ of following stirring reaction 5 hours, room temperature continue to decrease mixes reaction 12 hours.In reaction solution, add the 0.5mL saturated sodium bicarbonate solution, concentrating under reduced pressure, with purification by silica gel column chromatography (eluent: gained resistates system C), obtain title product (S)-1-(4-fluorophenyl)-2-methoxy ethyl carboxylamine tertiary butyl ester 3e (1.80g, white solid), productive rate: 86.0%.

MS?m/z(ESI)：170[M-C ₅H ₉O ₂]

The 5th step

(S)-1-(4-fluorophenyl)-2-methoxyethyl amine hydrochloride

Under the ice bath, with (S)-1-(4-fluorophenyl)-2-methoxy ethyl carboxylamine tertiary butyl ester 3e (2.30g, 8.5mmol) be dissolved in the 15mL tetrahydrofuran (THF), drip 25mL tetrahydrofuran (THF) and concentrated hydrochloric acid (V/V=3: 2) mixed solvent, stirring at room reaction 12 hours.Concentrating under reduced pressure adds 50mL toluene, and concentrating under reduced pressure obtains title product (S)-1-(4-fluorophenyl)-2-methoxyethyl amine hydrochloride 3f (1.60g, white needles solid), productive rate: 94.0% once more.

MS?m/z(ESI)：170[M+1]

The 6th step

(3S, 5S, 6S, 8S)-and 8-((S)-1-(4-fluorophenyl)-2-methoxy ethyl carbamyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester

Under the ice bath, with (S)-1-(4-fluorophenyl)-2-methoxyethyl amine hydrochloride 3f (0.25g, 1.2mmol) be dissolved in the 5mL toluene, drip the toluene solution and the 5mL (1S of the trimethyl aluminium of 0.6mL2M, 3S)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-4-methyl amyl carboxylamine tertiary butyl ester 1g (200mg, toluene solution 0.37mmol), stirring reaction 12 hours.In reaction solution, add 2mL 1M hydrochloric acid, with dichloromethane extraction (30mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product (3S with purification by silica gel column chromatography, 5S, 6S, 8S)-8-((S)-1-(4-fluorophenyl)-2-methoxy ethyl carbamyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 3g (90mg, Off-white solid), productive rate: 35.0%.

MS?m/z(ESI)：705[M+1]

The 7th step

Under the ice bath, with (3S, 5S, 6S, 8S)-8-((S)-1-(4-fluorophenyl)-2-methoxy ethyl carbamyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 3g (90mg, 0.12mmol) be dissolved in the 2mL methylene dichloride, add 4mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH＞7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, (eluent: the gained resistates system A of suitable proportion) obtains title product (2S, 4S to prepare the plate purifying with thin layer, 5S, 7S)-and 5-amino-N-((S)-1-(4-fluorophenyl)-2-methoxy ethyl)-4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide 3 (45mg, white oily matter), productive rate: 62.0%.

MS?m/z(ESI)：605[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)δ7.40(dd，J＝8.8Hz，5.6Hz，2H)，7.08(m，3H)，6.80(s，1H)，6.77-6.71(m，2H)，5.12(m，1H)，4.13(t，J＝6.4Hz，2H)，3.83(s，3H)，3.72-3.58(m，4H)，3.39-3.30(m，7H)，2.61(br.s，1H)，2.50-2.41(m，2H)，2.30(t，J＝8.8Hz，1H)，2.10(m，3H)，1.80(m，2H)，1.70(m，2H)，1.50(m，2H)，1.00-0.81(m，12H)

Embodiment 4

(2S, 4S, 5S, 7S)-5-amino-N-((S)-2-oxyethyl group-1-phenylethyl)-4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide

The first step

(S)-2-amino-2-phenylacetic acid carbethoxy hydrochloride

Under the ice bath, (7.90g 52.3mmol) is dissolved in the 100mL ethanol, and (4.60mL, 62.8mmol), stirring at room was reacted 2 hours, reflux 2 hours to drip thionyl chloride with (S)-2-amino-2-phenylacetic acid 1a.The reaction solution concentrating under reduced pressure obtains title product (S)-2-amino-2-phenylacetic acid carbethoxy hydrochloride 4a (9.40g, white solid) crude product.

Second step

(S)-2-(t-butoxycarbonyl amino)-2-phenylacetic acid ethyl ester

Under the ice bath, (9.36g 52.3mmol) is dissolved in the 100mL saturated sodium bicarbonate solution, adds 50mL two dimethyl dicarbonate butyl ester (17.11g with (S)-2-amino-2-phenylacetic acid carbethoxy hydrochloride 4a, 78.5mmol) dichloromethane solution, stirring reaction is 12 hours under the room temperature.Separatory, with dichloromethane extraction (150mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, obtain title product (S)-2-(t-butoxycarbonyl amino)-2-phenylacetic acid ethyl ester 4b (14.60g, colourless liquid) crude product.

MS?m/z(ESI)：302[M+23]

The 3rd step

(S)-2-hydroxyl-1-phenylethyl carboxylamine tertiary butyl ester

Under the ice bath, (15.0g 53.8mmol) is dissolved in the 150mL ethanol, and (8.13g, 43mmol), stirring reaction is 3.5 hours under the room temperature to add sodium borohydride with (S)-2-(t-butoxycarbonyl amino)-2-phenylacetic acid ethyl ester 4b.The reaction solution concentrating under reduced pressure, add 50mL water and 50mL ethyl acetate, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with purification by silica gel column chromatography (eluent: the gained resistates system B of suitable proportion), obtain title product (S)-2-hydroxyl-1-phenylethyl carboxylamine tertiary butyl ester 4c (12.00g, white solid) crude product.

MS?m/z(ESI)：260[M+23]

The 4th step

(S)-2-oxyethyl group-1-phenylethyl carboxylamine tertiary butyl ester

Under the ice bath, with (S)-2-hydroxyl-1-phenylethyl carboxylamine tertiary butyl ester 4c (2.37g, 10mmol) be dissolved in 10mLN, in the dinethylformamide, and the sodium hydride of adding 60% (0.52g, 13mmol), stirring reaction 15 minutes, (2.34g, 15mmol), room temperature continued stirring reaction 2 hours to add iodoethane.In reaction solution, add 2mL water, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product (S)-2-oxyethyl group-1-phenylethyl carboxylamine tertiary butyl ester 4d (1.20g with purification by silica gel column chromatography, white solid), productive rate: 45.4%.

The 5th step

(S)-2-oxyethyl group-1-phenyl-ethyl amine hydrochloride

Under the ice bath, (1.30g, (V/V=1: 1) in the mixing solutions, stirring at room was reacted 12 hours 5mmol) to be dissolved in 6mL tetrahydrofuran (THF) and concentrated hydrochloric acid with (S)-2-oxyethyl group-1-phenylethyl carboxylamine tertiary butyl ester 4d.Concentrating under reduced pressure adds 50mL toluene, and concentrating under reduced pressure obtains title product (S)-2-oxyethyl group-1-phenyl-ethyl amine hydrochloride 4e (1.10g, faint yellow solid) crude product once more.

The 6th step

(3S, 5S, 6S, 8S)-and 8-((S)-2-oxyethyl group-1-phenylethyl carbamyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester

Under the ice bath, with (S)-2-oxyethyl group-1-phenyl-ethyl amine hydrochloride 4e (242mg, 1.2mmol) be dissolved in the 5mL toluene, drip the toluene solution and the 5mL (1S of the trimethyl aluminium of 0.6mL 2M, 3S)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-4-methyl amyl carboxylamine tertiary butyl ester 1g (200mg, toluene solution 0.37mmol), stirring reaction 12 hours.In reaction solution, add 2mL 1M hydrochloric acid, with dichloromethane extraction (30mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product (3S with purification by silica gel column chromatography, 5S, 6S, 8S)-8-((S)-2-oxyethyl group-1-phenylethyl carbamyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 4f (90mg, faint yellow solid), productive rate: 34.4%.

MS?m/z(ESI)：701[M+1]

The 7th step

Under the ice bath, with (3S, 5S, 6S, 8S)-8-((S)-2-oxyethyl group-1-phenylethyl carbamyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 4f (90mg, 0.13mmol) be dissolved in the 2mL methylene dichloride, add 4mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH＞7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, (eluent: the gained resistates system A of suitable proportion) obtains title product (2S, 4S to prepare the plate purifying with thin layer, 5S, 7S)-and 5-amino-N-((S)-2-oxyethyl group-1-phenylethyl)-4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide 4 (50mg, colorless oil), productive rate: 65.0%.

MS?m/z(ESI)：601[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)δ7.43-7.27(m，5H)，6.79-6.65(m，4H)，5.23(m，1H)，4.11(t，J＝6.SHz，2H)，3.86(s，3H)，3.70(m，2H)，3.59(t，J＝6.4Hz，2H)，3.58-3.47(m，2H)，3.39(s，3H)，2.89(m，1H)，2.43(m，2H)，2.12(m，3H)，1.89(m，1H)，1.69-1.62(m，4H)，.45-1.33(m，2H)，1.20(t，J＝6.8Hz，2H)，1.02(m，1H)，0.98-0.83(m，12H)

Embodiment 5

(2S, 4S, 5S, 7S)-5-amino-N-((S)-2-oxyethyl group-1-(4-fluorophenyl) ethyl)-4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide fumarate

The first step

(S)-2-oxyethyl group-1-(4-fluorophenyl) ethyl carbamic acid tertiary butyl ester

Under the ice bath, with (S)-1-(4-fluorophenyl)-2-hydroxyethyl carboxylamine tertiary butyl ester 3d (3.02g, 12mmol) be dissolved in 20mLN, in the dinethylformamide, and the sodium hydride of adding 60% (0.61g, 15mmol), stirring reaction 30 minutes, (2.35g, 15mmol), room temperature continued stirring reaction 12 hours to add iodoethane.In reaction solution, add 2mL water, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product (S)-2-oxyethyl group-1-(4-fluorophenyl) ethyl carbamic acid tertiary butyl ester 5a (3.00g with purification by silica gel column chromatography, pale yellow crystals), productive rate: 88.0%.

MS?m/z(ESI)：184[M-C ₅H ₉O ₂]

Second step

(S)-2-oxyethyl group-1-(4-fluorophenyl) ethylamine hydrochloride

Under the ice bath, (3.00g, (V/V=3: 1) in the mixing solutions, stirring at room was reacted 12 hours 10.6mmol) to be dissolved in 40mL tetrahydrofuran (THF) and concentrated hydrochloric acid with (S)-2-oxyethyl group-1-(4-fluorophenyl) ethyl carbamic acid tertiary butyl ester 5a.Concentrating under reduced pressure adds 50mL toluene, and concentrating under reduced pressure obtains title product (S)-2-oxyethyl group-1-(4-fluorophenyl) ethylamine hydrochloride 5b (2.81g, buff powder), productive rate: 85.0% once more.

The 3rd step

(3S, 5S, 6S, 8S)-and 8-((S)-2-oxyethyl group-1-(4-fluorophenyl) ethylamino formyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester

Under the ice bath, with (S)-2-oxyethyl group-1-(4-fluorophenyl) ethylamine hydrochloride 5b (500mg, 2.3mmol) be dissolved in the 10mL toluene, drip the toluene solution and the 10mL (1S of the trimethyl aluminium of 1.2mL2M, 3S)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-4-methyl amyl carboxylamine tertiary butyl ester 1g (400mg, toluene solution 0.74mmol), stirring reaction 12 hours.In reaction solution, add 5mL1M hydrochloric acid, with dichloromethane extraction (30mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product (3S with purification by silica gel column chromatography, 5S, 6S, 8S)-8-((S)-2-oxyethyl group-1-(4-fluorophenyl) ethylamino formyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 5c (160mg, white solid), productive rate: 30.0%.

MS?m/z(ESI)：719[M+1]

The 4th step

(2S, 4S, 5S, 7S)-5-amino-N-((S)-2-oxyethyl group-1-(4-fluorophenyl) ethyl)-4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide

Under the ice bath, with (3S, 5S, 6S, 8S)-8-((S)-2-oxyethyl group-1-(4-fluorophenyl) ethylamino formyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 5c (160mg, 0.22mmol) be dissolved in the 4mL methylene dichloride, add 8mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH＞7, with dichloromethane extraction (40mL * 3), merge organic phase, water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, (eluent: the gained resistates system A of suitable proportion) obtains title product (2S, 4S to prepare the plate purifying with thin layer, 5S, 7S)-and 5-amino-N-((S)-2-oxyethyl group-1-(4-fluorophenyl) ethyl)-4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide 5d (48mg, colorless oil), productive rate: 33.0%.

MS?m/z(ESI)：619[M+1]

The 5th step

With (2S, 4S, 5S, 7S)-5-amino-N-((S)-2-oxyethyl group-1-(4-fluorophenyl) ethyl) 4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide 5d (48mg, 0.078mmol) be dissolved in the 2mL methyl alcohol, (4.5mg, 0.039mmol) stirring reaction is 10 minutes to add fumaric acid.The reaction solution concentrating under reduced pressure, obtain title product (2S, 4S, 5S, 7S)-5-amino-N-((S)-2-oxyethyl group-1-(4-fluorophenyl) ethyl)-4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide fumarate 5 (51mg, faint yellow solid), productive rate: 97.1%.

MS?m/z(ESI)：619[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)δ7.41(m，2H)，7.08(m，3H)，6.83(s，1H)，6.75(m，2H)，5.10(m，1H)，4.13(m，2H)，3.83(s，3H)，3.68-3.50(m，6H)，3.38(m，1H)，3.36(s，3H)，2.62(b?r.s，1H)，2.52-2.46(m，2H)，2.30(m，1H)，2.09(m，3H)，1.19(t，J＝7.2Hz，3H)，0.98-0.81(m，12H)

Embodiment 6

(2S, 4S, 5S, 7S)-5-amino-4-hydroxy-N-((S)-2-hydroxyl-1-phenylethyl)-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide

The first step

(S)-2-amino-2-phenylethyl alcohol

Under the ice bath, with lithium aluminum hydride (2.51g 66mmol) is dissolved in the 150mL tetrahydrofuran (THF), drip (S)-2-amino-2-phenylacetic acid 1a (5.02g, 33mmol), stirring reaction 30 minutes, 45 ℃ were continued stirring reaction 3 hours down.In reaction solution, add the less water cancellation, add the sodium hydroxide solution of 2.5mL15% and the water of 7.5mL, filter, concentrating under reduced pressure, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (S)-2-amino-2-phenylethyl alcohol 6a (2.31g, white solid), productive rate: 51.0%.

Second step

(3S, 5S, 6S, 8S)-and 6-hydroxyl-8-(hydroxymethyl)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester

Under the ice bath, with (1S, 3S)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-4-methyl amyl carboxylamine tertiary butyl ester 1g (800mg, 1.49mmol) be dissolved in the 15mL tetrahydrofuran (THF), the adding lithium aluminum hydride (170mg, 4.48mmol), stirring reaction 3 hours.In reaction solution, add the small amount of methanol cancellation, concentrating under reduced pressure, with silica gel column chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3S, 5S, 6S, 8S)-6-hydroxyl-8-(hydroxymethyl)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 6b (750mg, colorless oil), productive rate: 93.0%.

MS?m/z(ESI)：540[M+1]

The 3rd step

(3S, 5S, 6S, 8S)-and 8-((tert-butyl diphenyl siloxy) methyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester

With (3S, 5S, 6S, 8S)-and 6-hydroxyl-8-(hydroxymethyl)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2, (750mg 1.39mmol) is dissolved in the 15mL methylene dichloride 9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 6b, add phenylbenzene tertiary butyl chloride silane 6c (458mg, 1.67mmol) and imidazoles (94mg, 1.39mmol), stirring reaction 12 hours.In reaction solution, add the less water cancellation, with dichloromethane extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated sodium-chloride washing (20mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product (3S with the silica gel column chromatography purifying, 5S, 6S, 8S)-8-((tert-butyl diphenyl siloxy) methyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2,9-dimethyl decyl-5-aminocarbamic acid tertiary butyl ester 6d (1.03g, colorless oil), productive rate: 95.0%.

MS?m/z(ESI)：801[M+23]

The 4th step

(4S, 5S)-5-((S)-2-((tert-butyl diphenyl siloxy) methyl)-3-methyl butyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-3-carboxylic acid tertiary butyl ester

With (3S, 5S, 6S, 8S)-and 8-((tert-butyl diphenyl siloxy) methyl)-6-hydroxyl-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-2, the 9-dimethyl decyl-(1.03g 4.11mmol) is dissolved in 20mL2 to 5-aminocarbamic acid tertiary butyl ester 6d, in the 2-Propanal dimethyl acetal, adding tosic acid hydrate (78mg, 0.41mmol), stirring reaction 12 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH＞7, concentrating under reduced pressure, with dichloromethane extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated sodium-chloride washing (20mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product (4S, 5S)-5-((S)-2-((tert-butyl diphenyl siloxy) methyl)-3-methyl butyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-3-carboxylic acid tertiary butyl ester 6e (1.01g, colorless oil), productive rate: 93.0%.

MS?m/z(ESI)：840[M+23]

The 5th step

(4S, 5S)-5-(S)-2-(hydroxymethyl)-3-methyl butyl)-4-(S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-3-carboxylic acid tertiary butyl ester

With (4S, 5S)-5-(S)-2-((tert-butyl diphenyl siloxy) methyl)-3-methyl butyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-3-carboxylic acid tertiary butyl ester 6e (1.01g, 1.23mmol) be dissolved in the 25mL tetrahydrofuran (THF), add tetrabutyl ammonium fluoride (0.58g, 1.84mmol), stirring reaction 24 hours.In reaction solution, add the less water cancellation, with dichloromethane extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated sodium-chloride washing (50mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product (4S, 5S)-5-((S)-2-(hydroxymethyl)-3-methyl butyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-3-carboxylic acid tertiary butyl ester 6f (680mg, colorless oil), productive rate: 95.0%.

MS?m/z(ESI)：602[M+23]

The 6th step

(S)-2-(((4S, 5S)-3-(tertbutyloxycarbonyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-5-yl) methyl)-3 Methylbutanoic acid

With (4S, 5S)-5-((S)-2-(hydroxymethyl)-3-methyl butyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-3-carboxylic acid tertiary butyl ester 6f (300mg, 0.52mmol) be dissolved in the 8mL methylene dichloride, add N-methylmorpholine-N-oxide compound (94mg, 0.78mmol) and molecular sieve, stirred 10 minutes, add tetrapropyl perruthenate (9mg, 0.026mmol), stirring reaction 30 minutes is used S-WAT, saturated aqueous common salt successively, copper sulfate and saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates.

Under the ice bath, with above-mentioned gained resistates be dissolved in 20mL toluene and water (V/V=1: 1) in the mixed solvent, add potassium permanganate (448mg, 2.83mmol) and Tetrabutyl amonium bromide (56mg, 0.17mmol), stirring reaction 12 hours.The metabisulfite solution of Dropwise 5 0mL10% in reaction solution, add the saturated citric acid solution of 50mL, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated sodium-chloride washing (50mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product (S)-2-(((4S, 5S)-and 3-(tertbutyloxycarbonyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-5-yl) methyl)-3 Methylbutanoic acid 6g (320mg, brown oil) crude product.

The 7th step

(4S, 5S)-5-((S)-2-((S)-2-hydroxyl-1-phenylethyl carbamyl)-3-methyl butyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-3-carboxylic acid tertiary butyl ester

With (S)-2-(((4S, 5S)-3-(tertbutyloxycarbonyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-5-yl) methyl)-3 Methylbutanoic acid 6g (100mg, 0.17mmol) be dissolved in the 3mL acetonitrile, add diisopropylethylamine (0.05mL, 0.17mmol) and benzotriazole-N, N, N ', and N '-tetramethyl-urea phosphofluoric acid ester (64mg, 0.17mmol), stirring reaction 10 minutes, (25mg 0.19mmol), continued stirring reaction 12 hours to add (S)-2-amino-2-phenylethyl alcohol 6a.In reaction solution, add the less water cancellation, with dichloromethane extraction (30mL * 3), merge organic phase, water (10mL * 2) and saturated sodium-chloride washing (10mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (4S, 5S)-5-((S)-2-((S)-2-hydroxyl-1-phenylethyl carbamyl)-3-methyl butyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-3-carboxylic acid tertiary butyl ester 6h (60mg, white solid), productive rate: 50.0%.

The 8th step

Under the ice bath, with (4S, 5S)-5-((S)-2-((S)-2-hydroxyl-1-phenylethyl carbamyl)-3-methyl butyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-3-carboxylic acid tertiary butyl ester 6h (60mg, 0.084mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH＞7, with dichloromethane extraction (10mL * 3), merge organic phase, water (5mL * 2) and saturated sodium-chloride washing (5mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, (eluent: the gained resistates system A of suitable proportion) obtains title product (2S, 4S to prepare the plate purifying with thin layer, 5S, 7S)-and 5-amino-4-hydroxy-N-((S)-2-hydroxyl-1-phenylethyl)-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide 6 (30mg, white solid), productive rate: 62.5%.

MS?m/z(ESI)：573[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)δ7.35(dd，J＝5.6Hz，8.4Hz，2H)，7.20(br?s，1H)，1.09(t，J＝8.4Hz，2H)，6.82(s，1H)，6.75(d，J＝8.4Hz，1H)，6.70(d，J＝8.4Hz，1H)，4.96(m，1H)，4.11(t，J＝6.0Hz，2H)，3.92-3.83(m，2H)，3.79(s，3H)，3.67(m，1H)，3.58(t，J＝6.0Hz，2H)，3.53(s，3H)，3.35(s，3H)，2.88(br?s，1H)，2.45(m，2H)，2.29(t，J＝8.8Hz，1H)，2.08(m，2H)，1.80-1.35(m，7H)，0.92-0.83(m，12H)

Embodiment 7

(2S, 4S, 5S, 7S)-5-amino-N-((S)-1-(4-fluorophenyl)-2-hydroxyethyl)-4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide

The first step

(S)-2-amino-2-(4-fluorophenyl) ethanol

Under the ice bath, (2.51g, (V/V=1: 1) in the mixed solvent, stirring at room was reacted 12 hours 9.8mmol) to be dissolved in 30mL tetrahydrofuran (THF) and concentrated hydrochloric acid with (S)-1-(4-fluorophenyl)-2-hydroxyethyl carboxylamine tertiary butyl ester 3d.Concentrating under reduced pressure, add saturated sodium carbonate solution and regulate pH＞10, with ethyl acetate extraction (30mL * 3), merge organic phase, successively water (20mL * 2) and saturated sodium-chloride washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product (S)-2-amino-2-(4-fluorophenyl) ethanol 7a (1.20g, white solid), productive rate: 79.0%.

MS?m/z(ESI)：156[M+1]

Second step

(4S, 5S)-and 5-((S)-2-((S)-1-(4-fluorophenyl)-2-hydroxyethyl carbamyl)-3-methyl butyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-3-carboxylic acid tertiary butyl ester

With (S)-2-(((4S, 5S)-3-(tertbutyloxycarbonyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-5-yl) methyl)-3 Methylbutanoic acid 6g (400mg, 0.68mmol) be dissolved in the 20mL acetonitrile, add diisopropylethylamine (0.2mL, 0.68mmol) and benzotriazole-N, N, N ', and N '-tetramethyl-urea phosphofluoric acid ester (0.26g, 0.68mmol), stirring reaction 10 minutes, (0.12g 0.75mmol), continued stirring reaction 12 hours to add (S)-2-amino-2-(4-fluorophenyl) ethanol 7a.Concentrating under reduced pressure, with ethyl acetate extraction (30mL * 3), merge organic phase, water (10mL * 2) and saturated sodium-chloride washing (10mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (4S, 5S)-5-((S)-2-((S)-1-(4-fluorophenyl)-2-hydroxyethyl carbamyl)-3-methyl butyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-3-carboxylic acid tertiary butyl ester 7b (300mg, colorless solid), productive rate: 60.0%.

MS?m/z(ESI)：731[M+1]

The 3rd step

Under the ice bath, with (4S, 5S)-5-((S)-2-((S)-1-(4-fluorophenyl)-2-hydroxyethyl carbamyl)-3-methyl butyl)-4-((S)-2-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-3-methyl butyl)-2,2-dimethyl oxazolidine-3-carboxylic acid tertiary butyl ester 7b (300mg, 0.41mmol) be dissolved in the 12mL methylene dichloride, add 24mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 3 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH＞9, with dichloromethane extraction (30mL * 3), merge organic phase, water (10mL * 2) and saturated sodium-chloride washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, (eluent: the gained resistates system A of suitable proportion) obtains title product (2S, 4S to prepare the plate purifying with thin layer, 5S, 7S)-and 5-amino-N-((S)-1-(4-fluorophenyl)-2-hydroxyethyl)-4-hydroxyl-2-sec.-propyl-7-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-8-methyl pelargonamide 7 (110mg, white solid), productive rate: 46.0%.

MS?m/z(ESI)：591[M+1]

¹H?NMR(400MHz，CDCl ₃，ppm)δ7.37-7.23(m，5H)，6.81(d，J＝1.6Hz，1H)，6.74(m，1H)，6.68(d，J＝8.4Hz，1H)，5.00(dd，J＝12.4Hz，6.8Hz，1H)，4.10(t，J＝6.4Hz，2H)，3.88(d，J＝5.6Hz，2H)，3.77(s，3H)，3.64(t.J＝8.8Hz，1H)，3.57(t，J＝6.0Hz，2H)，3.34(s，3H)，2.87(m，1H)，2.46(d，J＝7.2Hz，2H)，2.30(t，J＝8.8Hz，1H)，2.07(m，2H)，1.81-1.37(m，7H)，0.91-0.79(m，12H)

Test case:

Biological assessment

Test case 1, The compounds of this invention suppress the renin activity test

Following method is to be used for measuring the inhibition ability of invention compound to the feritin protease activity.The half-inhibition concentration IC of each compound ₅₀(enzymic activity is suppressed to 50% o'clock compound concentrations of surveying) is to be used for measuring with the substrate of the enzyme Mixed Stationary amount of fixed amount and the testing compound of different concns.

The compounds of this invention suppresses the mensuration of renin activity

Material:

1. black 96 orifice plates (Greiner bio-one#655087)

2.10X damping fluid

The 1X damping fluid

50mM?Tris-HCl

100mM?NaCl

pH?8.0

(Cayman#10006870)

3.Renin enzyme (sigma-aldrich#R2779)

4.Renin substrate (Cayman#100068720)

5.ddH ₂O

(6.DMSO traditional Chinese medicines #30072418)

Method:

Undertaken by following working order:

1. with 50% DMSO (DMSO: ddH ₂O, 1: 1) compound is diluted in advance the final concentration that needs.

2. use ddH ₂O is diluted to the 1X damping fluid with the 10X damping fluid.37 ℃ of preheating 1X damping fluids.

3.Blank (blank group)-Jia 10 μ L substrates, 80 μ L 1X damping fluids, 5uL50%DMSO are established the contrast of multiple hole to every hole.

4.Negative control (100% active control group)-Jia 10 μ L substrates, 75 μ L 1X damping fluids, 5 μ L 50%DMSO establish the contrast of multiple hole to every hole.

5.Sample (test-compound group)-Jia 10 μ L substrates, 75 μ L1X damping fluids, 5 μ L compounds (being dissolved in 50%DMSO) are established the contrast of multiple hole to every hole.

6. dilute the Renin enzyme to 8.33ng/ μ L with the 1X damping fluid.

7. add 5 μ L Renin to Negative control reacting holes and Sample reacting hole and start reaction.Micro oscillator shake 10 second mixing, shrouding film shrouding was hatched 90 minutes for 37 ℃.

8. remove the shrouding film, under excitation wavelength 335～345nm and emission wavelength 485～510nm condition, read fluorescent value.

Inhibiting rate calculates:

IR(％)＝100-100*(S-B)/(N-B)

S=adds the fluorescent value of the reacting hole of test compounds

The fluorescent value of N=negative control reacting hole

The fluorescent value of B=blank well

IC ₅₀Value can be calculated by the IR value of test compounds under concentration gradient and get.

The activity of The compounds of this invention

The biochemical activity of The compounds of this invention is measured by above test, the IC that records ₅₀Value sees the following form.

The embodiment compound	IC ₅₀Value (nM)
		1	1
3	2
		5	1

Conclusion: the IC of compound of the present invention ₅₀Value is 1～2nM, and it all has inhibition significantly active to feritin proteolytic enzyme.

Pharmacokinetics is estimated

The pharmacokinetics test of test case 2, The compounds of this invention

1, summary

With the rat is animal subject, uses the LC/MS/MS method and measures rat oral gavage and give the drug level in the different moment blood plasma behind embodiment 1 and embodiment 5 compounds.The research The compounds of this invention is estimated its characteristics of pharmacokinetics in the pharmacokinetics in rats behavior.

2. operation

Take by weighing a certain amount of medicine, add 0.5% Xylo-Mucine and be mixed with the 3.0mg/mL suspension.

8 of healthy adult SD rats, male and female half and half, 4 every group, difference gastric infusion behind the overnight fasting, dosage is 30.0mg/kg.

Gastric infusion after one night of fasting, dosage is 30.0mg/kg, embodiment 1 and embodiment 5 are before administration and after the administration 0.5,1.0,2.0,3.0,4.0,6.0,8.0,12.0,24.0,36.0,48.0, placed the heparinization test tube by eye socket blood sampling 0.2mL in 72.0 hours, 4 ℃, 10000 rev/mins centrifugal 10 minutes separated plasmas, in-20 ℃ of preservations, feed in 2 hours after the administration.

Measure the testing compound in the rat plasma behind the medicine gastric infusion of different concns: draw each rat plasma 50 μ L constantly behind the medicine, add inner mark solution 50 μ L, methyl alcohol 100 μ L, vortex mixed 3 minutes, centrifugal 10 minutes (13500 rev/mins) are got supernatant liquor 10 μ L and are carried out the LC/MS/MS analysis.

3, pharmacokinetic parameter result

The pharmacokinetic parameter of The compounds of this invention is as follows:

Conclusion: the medicine of The compounds of this invention is good for absorbing, and has tangible pharmacokinetics advantage.

Claims

1. the compound shown in the general formula (I) or its pharmacy acceptable salt:

Wherein:

Ring A is selected from aryl or heteroaryl;

R ²Be selected from hydrogen atom or alkyl;

R ³Be selected from hydrogen atom or alkyl;

R ⁸Or R ⁹Be selected from hydrogen atom or alkyl separately;

R ¹⁰Be selected from hydrogen atom, alkyl or aryl;

R ¹¹Or R ¹²Be selected from hydrogen atom or alkyl separately; And

N is 0,1 or 2.

2. compound according to claim 1 or its pharmacy acceptable salt comprise the compound shown in the following general formula (II) or its pharmacy acceptable salt:

Wherein:

Ring A is selected from aryl or heteroaryl;

R ²Be selected from hydrogen atom or alkyl;

R ³Be selected from hydrogen atom or alkyl;

R ⁸Or R ⁹Be selected from hydrogen atom or alkyl separately;

R ¹⁰Be selected from hydrogen atom, alkyl or aryl;

R ¹¹Or R ¹²Be selected from hydrogen atom or alkyl separately; And

N is 0,1 or 2.

3. according to each described compound of claim 1～2 or its pharmacy acceptable salt, wherein said compound comprises:

4. preparation method who prepares compound according to claim 1 or its pharmacy acceptable salt, this method comprises:

General formula (IA) compound and replacement primary amine reaction, and under suitable condition, comprise the protecting group PG that sloughs amine under alkaline condition, acidic conditions or the catalytic hydrogenation condition, obtain general formula (I) compound,

Wherein: ring A, R ¹～R ⁷Definition according to claim 1; PG is the amido protecting group, is selected from tert-butoxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, trifluoroacetyl group, formyl radical, p-toluenesulfonyl, trityl, phthalimide-based or 2-xenyl-2-third oxygen carbonyl, is preferably tert-butoxycarbonyl.

5. method according to claim 4, this method comprises:

General formula (IB) compound and replacement primary amine reaction, and under suitable condition, comprise the protecting group PG that sloughs amine under alkaline condition, acidic conditions or the catalytic hydrogenation condition, obtain general formula (II) compound,

Wherein: ring A, R ¹～R ⁷Definition as described in the claim 2; PG is the amido protecting group, is selected from tert-butoxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, trifluoroacetyl group, formyl radical, p-toluenesulfonyl, trityl, phthalimide-based or 2-xenyl-2-third oxygen carbonyl, is preferably tert-butoxycarbonyl.

6. according to each described compound of claim 1～3 or its pharmacy acceptable salt purposes in the medicine of preparation renin inhibitor.

7. according to each described compound of claim 1～3 or its pharmacy acceptable salt, wherein pharmacy acceptable salt is compound and is selected from following sour formed salt: oxysuccinic acid, lactic acid, toxilic acid, hydrochloric acid, methylsulfonic acid, sulfuric acid, phosphoric acid, citric acid, fumaric acid, acetate or trifluoroacetic acid are preferably fumaric acid.

8. pharmaceutical composition, its contain the treatment effective dose according to each described compound of claim 1～3 or its pharmacy acceptable salt, and pharmaceutically acceptable carrier or vehicle.

9. according to each described compound of claim 1～3 or its pharmacy acceptable salt, the purposes of pharmaceutical composition according to claim 5 in the medicine of preparation treatment and renin activity diseases associated.

10. purposes according to claim 9, wherein said and renin activity diseases associated is selected from: hypertension, atherosclerosis, the instability mode coronary syndrome, congestive heart failure, myocardial hypertrophy, myocardial fibrosis, infraction back myocardosis, the instability mode coronary syndrome, diastolic dysfunction, chronic nephropathy, hepatic fibrosis, the complication that diabetes cause, coronary artery disease, the restenosis of postangioplasty, eye-chamber pressure raises, glaucoma, the abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimer's disease, dull-witted, anxiety state or cognitive disorders, the complication that wherein said diabetes cause comprises ephrosis, vascular disease and neuropathy.

11. the purposes of pharmaceutical composition according to claim 8 in the medicine of preparation renin inhibitor.